The goal is to develop an understanding of the basic regulatory mechanisms in neurons and endocrine cells which secrete peptides, and through this understanding, develop novel pharmacotherapeutic approaches and agents for manipulating peptidergic neuronal and endocrine systems. Two projects are ongoing. The first studies the regulation of biosynthesis of peptides. The primary model investigated is the neuronal and endocrine opioid system which secretes ACTH, Alpha-MSH, and Beta-endorphin peptides all derived from a common prohormone, pro-opiomelanocortin (POMC). Our investigations indicate that regulation of POMC gene expression occurs primarily at the transcriptional level. The expression of POMC and processing enzyme genes appear to be regulated by cAMP-protein kinase A and diacylglycerol-protein kinase C mediated mechanisms. We have identified a number of putative third messenger phosphoproteins which may link cell surface receptors to transcriptional mechanisms in the nucleus. The second investigation is focused on studies of the phencyclidine (PCP) and sigma opioid receptors and two endogenous ligands, Alpha-endopsychosin and Beta-endopsychosin, which interacts with these receptors, respectively. The peptides were isolated from extracts of porcine brain based on the ability of the compound to inhibit the binding of PCP or SKF 10,047 to brain receptors. The Beta-endopsychosin was partially sequenced and peptide fragments were synthesized. These peptides had similar biological activity to SKF 10,047. Future studies will focus on the role of these peptides in neuro and pathophysiology.